More than 30 million Americans suffer from unrelieved chronic pain, which is regarded as a disease with its own pathology. Current studies focus on how pain is induced, but it is unclear how acute pain naturally resolves. We hypothesize that disruption of local active pro-resolving processing will result in chronic pain. Our recent studies have shown that the pro-resolution lipid mediators (PRLMs) such as resolvins and protectins, derived from omega-3 unsaturated fatty acids DHA and EPA, are potent inhibitors of inflammatory and neuropathic pain. Mechanistically, PRLMs not only normalize synaptic plasticity but also suppress glial activation in the spinal cord. Resolvins are also potent endogenous inhibitors of TRPA1 or TRPV1 (IC50=1-10 nM). However, the signaling mechanisms of PRLMs are elusive. b-arrestin-2 (barr2) is a scaffold protein that is classically involved in desensitization of GPCRs. However, the unique role of barr2 in regulating NMDA receptor function and inflammatory/neuropathic pain is unknown. The overall goal of this application is to investigate how barr2 arrests pain and whether PRLMs resolve pain via barr2. Our central hypothesis is barr2, activated by some PRLMs, arrests pain and contributes to the resolution of inflammatory and neuropathic pain via masking ERK activation. We will test this hypothesis via the following specific aims: Aim 1, to establish that barr2 is essential for the resolution of inflammatory and neuropathic pain, and Aim 2, to define the peripheral and central roles of PRLMs and barr2 in pain resolution, by modulating TRPA1/V1 function in DRG neurons, NMDAR function in spinal cord neurons, and ERK activation in neurons and glia. We believe this proposal is highly significant by testing a novel pain resolution pathway mediated by PRLMs or/and barr2. Our approach is multidisciplinary that combines genetic manipulation (transgenic mice, conditional knockout mice, gene therapy), electrophysiology, and behavioral testing for evoked pain and spontaneous pain (CPP). We will also test the role of PRLMs in human DRG neurons to increase the translational potential. The proposed study will not only identify a pro- resolution pathway for pain arrest but may also lead to the development of novel pain therapeutics.